User:Alice Harmon/Sandbox 1: Difference between revisions

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The <scene name='55/555705/Activationloop/1'>activation loop</scene> was first described by Taylor and Radzio-Andzelm<ref> PMID:8081750 </ref>. It comprises amino acid residues between the DFG motif in subdomain VII to the APE motif in subdomain VIII. As it's name implies, it is involved in switching the activity of the kinase on and off. When the phosphorylatable residue in subdomain VIII (see above) is phosphorylated, the <scene name='55/555705/Activationloop/2'>activation loop is positioned</scene> such that the active site cleft is accessible, the magnesium loop (DFG motif) and catalytic loop (HRDLKPxxN motif) are properly positioned for catalysis, and the P+1 loop can interact with the peptide substrate. The activation loop takes on a variety of conformations in inactive kinases<ref> PMID:12015977 </ref>, that disrupt one or all of these conformations.

Two hydrophobic <scene name='55/555705/Both_spines/2'>"spines"</scene> (reviewed by Taylor and Kornev<ref="TaylorTIBS"> PMID: 20971646 </ref>) are important for the structure of active conformation of protein kinases. They are composed of amino acid residues that are non-contiguous in the primary structure. <scene name='55/555705/Spine1/1'> The catalytic spine </scene>includes the adenine ring of ATP. In PKA it comprises residues (from top to bottom in the scene) A70, V57, ATP, L173, I174, L172, M128, M231, and L227, and it is directly anchored to amino end of helix F (Subdomain IX) <scene name='55/555705/Spine2/1'>The regulatory spine</scene> contains residues L106, L95, F185, Y164, and it is anchored to helix F via a hydrogen bond between the invariant aspartate in helix F (yellow ball and stick) and the backbone nitrogen of Y164. This spine is assembled in the active conformation and disorganized in inactive conformations.

Two hydrophobic <scene name='55/555705/Both_spines/2'>"spines"</scene> (reviewed by Taylor and Kornev<ref name ="TaylorTIBS"> PMID: 20971646 </ref>) are important for the structure of active conformation of protein kinases. They are composed of amino acid residues that are non-contiguous in the primary structure. <scene name='55/555705/Spine1/1'> The catalytic spine </scene>includes the adenine ring of ATP. In PKA it comprises residues (from top to bottom in the scene) A70, V57, ATP, L173, I174, L172, M128, M231, and L227, and it is directly anchored to amino end of helix F (Subdomain IX) <scene name='55/555705/Spine2/1'>The regulatory spine</scene> contains residues L106, L95, F185, Y164, and it is anchored to helix F via a hydrogen bond between the invariant aspartate in helix F (yellow ball and stick) and the backbone nitrogen of Y164. This spine is assembled in the active conformation and disorganized in inactive conformations.

The <scene name='55/555705/Gatekeeper-subdomainv/2'>"gatekeeper"</scene> residue<ref name="TaylorTIBS"/> (chartreuse spacefill) is a part of subdomain V (blue) and it is located deep in the ATP-binding pocket (Subdomain I with its ATP binding loop are shown in yellow). The size of the gatekeeper residue determines the size of the binding pocket, and it is thus a gatekeeper for which nucleotides, ATP analogs, and inhibitors can bind<ref> PMID: 15908922 </ref>. In PKA and about 75% of all kinases it is a large residue, such as leucine, phenylalanine or methionine as seen here. In the remaining kinases, especially tyrosine kinases, the residue is larger, such as threonine or valine. The gatekeeper's location is <scene name='55/555705/Gatekeeper-spines/2'>between the two hydrophobic spines </scene><ref name="TaylorTIBS"/> (gatekeeper is chartreuse, catalytic spine is blue, regulatory spine is orchid). Mutation of this residue in some kinases leads to activation of the kinase via enhanced autophosphorylation of the activation loop, and the unregulated kinase activity promotes cancer PMID: 17114285 PMID: 18794843. The gatekeeper's interaction with the two spines affects the orientation of the catalytic and magnesium binding loops.

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 The <scene name='55/555705/Activationloop/1'>activation loop</scene> was first described by Taylor and Radzio-Andzelm<ref> PMID:8081750 </ref>. It comprises amino acid residues between the DFG motif in subdomain VII to the APE motif in subdomain VIII. As it's name implies, it is involved in switching the activity of the kinase on and off. When the phosphorylatable residue in subdomain VIII (see above) is phosphorylated, the <scene name='55/555705/Activationloop/2'>activation loop is positioned</scene> such that the active site cleft is accessible, the magnesium loop (DFG motif) and catalytic loop (HRDLKPxxN motif) are properly positioned for catalysis, and the P+1 loop can interact with the peptide substrate. The activation loop takes on a variety of conformations in inactive kinases<ref> PMID:12015977 </ref>, that disrupt one or all of these conformations.
-Two hydrophobic <scene name='55/555705/Both_spines/2'>"spines"</scene> (reviewed by Taylor and Kornev<ref="TaylorTIBS"> PMID: 20971646 </ref>) are important for the structure of active conformation of protein kinases. They are composed of amino acid residues that are non-contiguous in the primary structure. <scene name='55/555705/Spine1/1'> The catalytic spine </scene>includes the adenine ring of ATP. In PKA it comprises residues (from top to bottom in the scene) A70, V57, ATP, L173, I174, L172, M128, M231, and L227, and it is directly anchored to amino end of helix F (Subdomain IX)  <scene name='55/555705/Spine2/1'>The regulatory spine</scene> contains residues L106, L95, F185, Y164, and it is anchored to helix F via a hydrogen bond between the invariant aspartate in helix F (yellow ball and stick) and the backbone nitrogen of Y164. This spine is assembled in the active conformation and disorganized in inactive conformations.
+Two hydrophobic <scene name='55/555705/Both_spines/2'>"spines"</scene> (reviewed by Taylor and Kornev<ref name ="TaylorTIBS"> PMID: 20971646 </ref>) are important for the structure of active conformation of protein kinases. They are composed of amino acid residues that are non-contiguous in the primary structure. <scene name='55/555705/Spine1/1'> The catalytic spine </scene>includes the adenine ring of ATP. In PKA it comprises residues (from top to bottom in the scene) A70, V57, ATP, L173, I174, L172, M128, M231, and L227, and it is directly anchored to amino end of helix F (Subdomain IX)  <scene name='55/555705/Spine2/1'>The regulatory spine</scene> contains residues L106, L95, F185, Y164, and it is anchored to helix F via a hydrogen bond between the invariant aspartate in helix F (yellow ball and stick) and the backbone nitrogen of Y164. This spine is assembled in the active conformation and disorganized in inactive conformations.
 The <scene name='55/555705/Gatekeeper-subdomainv/2'>"gatekeeper"</scene> residue<ref name="TaylorTIBS"/> (chartreuse spacefill) is a part of subdomain V (blue) and it is located deep in the ATP-binding pocket (Subdomain I with its ATP binding loop are shown in yellow).  The size of the gatekeeper residue determines the size of the binding pocket, and it is thus a gatekeeper for which nucleotides, ATP analogs, and inhibitors can bind<ref> PMID: 15908922 </ref>. In PKA and about 75% of all kinases it is a large residue, such as leucine, phenylalanine or methionine as seen here. In the remaining kinases, especially tyrosine kinases, the residue is larger, such as threonine or valine.  The gatekeeper's location is <scene name='55/555705/Gatekeeper-spines/2'>between the two hydrophobic spines </scene><ref name="TaylorTIBS"/> (gatekeeper is chartreuse, catalytic spine is blue, regulatory spine is orchid). Mutation of this residue in some kinases leads to activation of the kinase via enhanced autophosphorylation of the activation loop, and the unregulated kinase activity promotes cancer PMID: 17114285 PMID: 18794843. The gatekeeper's interaction with the two spines affects the orientation of the catalytic and magnesium binding loops.